Major depression is the most prevalent mood disorder, yet there has not been major therapeutic progress in developing clinical treatments in the past 20 years. Most antidepressant strategies affect monoamine neurotransmitter systems with serotonin (5-HT) as the most common target. Recently, though, there has been a growing body of clinical and preclinical evidence that implicate the medial prefrontal cortex (mPFC) in depression and its treatment. Structural and functional imaging studies in patients have revealed consistent volume changes and hyperactivity of this region in mood disorders. Studies performed in animals have also shown that the neuroplastic changes in the mPFC may also be related to vulnerability and resiliency to stressors and depression-like behaviors. Additionally, deep brain stimulation (DBS) of the mPFC in both humans and animals produced an antidepressant-like effect. Interestingly, an intact 5-HT system was required for DBS to produce this effect. Previous work has shown that the mPFC sends projections to the dorsal raphe nucleus (DRN), which contains the largest population of 5-HT neurons in the brain. However, the DRN is heterogeneous and these projections actually appear to converge on GABAergic neurons, which suggests that these GABA neurons may act as filters of sensory control over 5-HT. Additionally, our lab and others have also shown that DRN GABA neurons are primarily activated in response to a variety of stressors, which would also suggest how dysregulation of this population might lead to mood disorders. The goal of this proposal is to show that neuroplastic adaptations mediated by DRN GABAergic neurons in the mPFC-DRN pathway affect depressive-like behaviors and antidepressant response. My first specific aim is to perform a neuroanatomical and functional dissection of the mPFC-DRN pathway and will allow me to better characterize the cellular architecture of this circuit. The second aim will use electrophysiological and morphological techniques to evaluate the adaptations induced by social stress in various cellular components of the mPFC-DRN pathway. In the third aim I will use optogenetic tools to dissect the behavioral impact of specific neural populations in the mPFC-DRN pathway in the social defeat model of depression. Together, these aims will provide a better understanding of the circuitry that underlies mood disorders and could lead to the development of more effective and efficient antidepressant strategies. PUBLIC HEALTH RELEVANCE: The proposed project will explore the functional cytoarchitecture of the pathway between the medial prefrontal cortex and the dorsal raphe nucleus and its role in depression-like behaviors. This work will investigate the physiological adaptations and behavioral contributions of specific neural populations that compose this circuit. Results from this work will contribute to the development of more effective and efficient antidepressant strategies.